Schistosomiasis is a major neglected helminthic disease suffered by over 200 million people throughout the world. Critical to understanding schistosomiasis is the notion that it represents an immunologically mediated disease, that is, the damage to the affected tissues is inflicted by the host's own immune system, rather than by the parasite itself. Thus, morbidity and mortality are largely due to a pathogenic CD4 T lymphocyte-mediated immune response against parasite egg antigens. This results in granulomatous and fibrosing inflammation, which in the case of the species Schistosoma mansoni, takes place in the liver and intestines. The magnitude of disease varies greatly from individual to individual. In the majority of cases there is relatively limited immunopathology with good survival, however, in a minority of patients there is severe disease and death. S. mansoni infection in a mouse model similarly results in marked strain variation of immunopathology. In CBA mice, severe hepatic inflammation is associated a novel subset of pathogenic CD4 T cells producing IL-17 (Th17 cells), of which an expanded, clonally-restricted subpopulation is specific for the immunodominant epitope 234-246 of the major Sm-p40 schistosome egg antigen (Sm-p40234-246). In contrast, C57BL/6 mice develop milder lesions within the context of a largely anti-inflammatory immune response. The objective of the present application is to investigate the mechanisms that underlie the development of the severe form of immunopathology embracing the hypothesis that this is precipitated by a distinct, genetically determined innate antigen-presenting cell (APC) reaction to parasite products resulting in the development of a pathogenic adaptive Th17 cell response. Aim 1 of the proposal is to ascertain by gene profiling, and functionally test by gene knock- down, the lectin receptors on APC that recognize specific parasite egg-derived glycoproteins leading to pathogenic Th17 cell differentiation in CBA mice. Aim 2 is to understand the role of Sm-p40-reactive T cells in mediating severe pathology by making use of novel mice expressing a transgenic Sm-p40-specific T cell receptor, or rendered unresponsive to Sm-p40 by virtue of transgenic expression of this antigen in the thymus. Aim 3 is a forward genetic analysis to identify relevant quantitative trait loci taking advantage of unique congenic strains between BL/10 and BL/6 mice, which differ in only 5% of their genome, and yet exhibit significantly dissimilar IL-17 production and hepatic egg-induced inflammation. The proposed studies will provide new insights into the mechanisms leading to severe immunopathology in schistosomiasis. Their ultimate objective is the design of focused, realistic and practical strategies for amelioration of disease, which could be amenable for consideration and implementation in the human patient population.